GeneBe

CLN3

protein-coding

CLN3 lysosomal/endosomal transmembrane protein, battenin

Gene summary

This gene encodes a protein that is involved in lysosomal function. Mutations in this, as well as other neuronal ceroid-lipofuscinosis (CLN) genes, cause neurodegenerative diseases commonly known as Batten disease or collectively known as neuronal ceroid lipofuscinoses (NCLs). Many alternatively spliced transcript variants have been found for this gene. [provided by RefSeq, Jul 2008]

Previous symbols:
  • BTS

MANE transcript

NM_001042432.2

Inheritance

AR

ClinVar variants

P:234U:326B:270

Top phenotype

Ceroid lipofuscinosis, neuronal, 3

gnomAD constraint

pLI —, LoF o/e 0.59

Max pathogenic AF

—

Genomic locus

chr16:28,474,111-28,495,575

External References & Databases

Ensembl (ENSG00000188603)NCBI Gene (1201)OMIM (607042)HGNC:2074GenCCUniProt (Q13286)AlphaFoldClinVar (CLN3)gnomADPubMedJAXSFARI

Transcript & Mutation Effects

hg38 • Region Span ~21.5 kb
Loading mutation effect viewer...

GenCC Phenotypes & Disease Associations

Curated gene-disease validity assertions and inheritance patterns

neuronal ceroid lipofuscinosisDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0016295

Submitter: ClinGen

*CLN3* was first reported in relation to autosomal recessive neuronal ceroid lipofuscinosis (NCL) in 1995 (Lerner et al., PMID:7553855; MONDO:0016295). NCL patients with variants in *CLN3* are typically diagnosed in childhood with gradual loss of vision that evolves into total blindness, epileptic seizures, muscular deterioration, and cognitive decline. There have been individuals reported with biallelic variants in *CLN3* and an isolated retinal phenotype; these individuals reached adulthood without the other characteristic features of NCL (PMID:24154662). It is unclear at this time how these cases relate to the classic NCL cases; this curation is exclusively for the relationship between CLN3 and NCL. Although many individuals with variants in *CLN3* have been reported in the literature, five variants (e.g. large deletion, missense, frameshift, stop gained and frameshift) from five probands in four publications are included in this curation (PMIDs: 31926949, 21499717, 19489875 and 19135632). Of note, the recurrent founder variant (a 1.02kb deletion resulting in the removal of exons 7 and 8 and a premature stop codon at exon 9) is the most frequently observed variant and is seen in approximately 96% of patients (PMID:35599949). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. In summary, there is a definitive relationship between *CLN3* and autosomal recessive neuronal ceroid lipofuscinosis. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date of April 4, 2023 (SOP Version 9).

neuronal ceroid lipofuscinosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: Genomics England PanelApp

neuronal ceroid lipofuscinosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: Myriad Women's Health

neuronal ceroid lipofuscinosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: Ambry Genetics

inherited retinal dystrophyDEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0019118

Submitter: G2P

neuronal ceroid lipofuscinosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: G2P

neuronal ceroid lipofuscinosis 3STRONG

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: Labcorp Genetics (formerly Invitae)

neuronal ceroid lipofuscinosis 3DEFINITIVE

Inheritance Pattern: AR

Disease ID:MONDO:0008767

Submitter: Natera

Clinical Genomic Database (CGD)

Ceroid lipofuscinosis, neuronal, 3AR

Manifestation: Biochemical; Neurologic; Ophthalmologic

Intervention: Neurologic

Rationale: Levodopa treatment may be beneficial

Refs: 7426545; 1609833; 1319116; 7553855; 7887420; 9004140; 9311735; 9450775; 10477428; 11342698; 15965709; 17947292; 19135632; 19489875; 21990111Source: CGD (NHGRI)

ClinVar Associated Diseases & Phenotypes

Reported disease conditions connected to CLN3 variants in ClinVar

18 Conditions Cataloged
Neuronal ceroid lipofuscinosisTotal: 942
Neuronal ceroid lipofuscinosis 3Total: 265
not providedTotal: 225
not specifiedTotal: 124
Inborn genetic diseasesTotal: 99
Juvenile neuronal ceroid lipofuscinosisTotal: 83
CLN3-related disorderTotal: 44
CLN3-related disordersTotal: 37

ClinVar Variants & Pathogenicity by Type

Statistics based on transcript NM_001042432.2. Only rare variants are included.

We include only reliable ClinVar variants with their consequences to MANE Select, MANE Plus Clinical transcripts, or transcripts with TSL equal to 1. Click a count to filter the variants table below.

Slight differences between displayed counts and ClinVar may occur due to a different transcript/consequence chosen by our variant effect predictor, or because we classify Benign/Likely benign as Likely benign and Pathogenic/Likely pathogenic as Likely pathogenic.

EffectPLPVUSLBBSum
synonymous
7
clinvar
260
clinvar
2
clinvar
 269
missense
2
clinvar
28
clinvar
309
clinvar
8
clinvar
 347
nonsense
21
clinvar
23
clinvar
 44
start loss
1
clinvar
3
clinvar
 4
frameshift
37
clinvar
51
clinvar
3
clinvar
 91
splice donor/acceptor (+/-2bp)
11
clinvar
57
clinvar
7
clinvar
 75
Total721623262682830

Highest pathogenic variant AF is 0.00016977865

Loading ClinVar variants...

Transcript Catalog

Annotated transcript isoforms across RefSeq and Ensembl databases

Showing 4 of 69 transcripts
Transcript IDSourceProtein IDCoding ExonsMANE Status
NM_001042432.2RefSeqNP_001035897.115MANE Select
ENST00000636147.2EnsemblENSP00000490105.115MANE Select
NM_000086.2RefSeqNP_000077.115Standard
NM_001286104.2RefSeqNP_001273033.114Standard

Model Organisms & Knockout Phenotypes

Observed phenotypic effects in mouse and zebrafish models

Gene / ModelOrganismObserved Phenotype
cln3Danio rerio

Structure: neuron

Quality: morphology

abnormal

Gene Ontology (GO) Annotations & Pathways

Biological processes, molecular functions, cellular components and pathways

Pathways ConsensusPathDB

  • Lysosome - Homo sapiens (human)

Biological Process

  • action potential
  • globoside metabolic process
  • cellular amino acid metabolic process
  • ceramide metabolic process
  • glucosylceramide metabolic process

Molecular Function

  • protein binding
  • unfolded protein binding

Cellular Component

  • Golgi membrane
  • nucleus
  • cytoplasm
  • mitochondrion
  • lysosome

gnomAD Constraint

Source: gnomAD

Gene type
protein_coding
Transcript type
protein_coding
Transcript
ENST00000569430
Coding exons
15
Length
28914
Individuals with no LoFs
125714
Homozygous LoFs
0
Heterozygous LoFs
34
Defined
125748
p
0.000135
Z-ScoreObservedExpectedObserved/ExpectedMutation RateTotal Possible
Missense-0.1462552491.030.00001542766
Missense (PolyPhen)106105.851.00151281
Synonymous-1.081291141.130.00000767946
Loss of Function1.931525.50.5880.00000122283

Population LoF Frequency

PopulationCAFp-valueStatus
African00.0absent
Latino/Admixed American0.0000580.000058rare
Ashkenazi Jewish00.0absent
East Asian0.000220.00022rare
Finnish0.0000960.000046rare
European (Non-Finnish)0.000210.00020rare
South Asian0.000130.00013rare
Other00.0absent

dbNSFP Gene Annotations

Source: dbNSFP

Function
FUNCTION: Involved in microtubule-dependent, anterograde transport of late endosomes and lysosomes. {ECO:0000269|PubMed:22261744}.;
Disease
DISEASE: Ceroid lipofuscinosis, neuronal, 3 (CLN3) [MIM:204200]: A form of neuronal ceroid lipofuscinosis. Neuronal ceroid lipofuscinoses are progressive neurodegenerative, lysosomal storage diseases characterized by intracellular accumulation of autofluorescent liposomal material, and clinically by seizures, dementia, visual loss, and/or cerebral atrophy. The hallmark of CLN3 is the ultrastructural pattern of lipopigment with a fingerprint profile, which can have 3 different appearances: pure within a lysosomal residual body; in conjunction with curvilinear or rectilinear profiles; and as a small component within large membrane-bound lysosomal vacuoles. The combination of fingerprint profiles within lysosomal vacuoles is a regular feature of blood lymphocytes from patients with neuronal ceroid lipofuscinosis type 3. {ECO:0000269|PubMed:21990111, ECO:0000269|PubMed:22261744, ECO:0000269|PubMed:9311735, ECO:0000269|PubMed:9490299}. Note=The disease is caused by mutations affecting the gene represented in this entry.;

Recessive Scores

pRec
0.284

Intolerance Scores

LoFtool
0.231
RVIS EVS
-0.16
RVIS percentile EVS
42.16

Essentials

Essential (CRISPR)
N
Essential (CRISPR2)
N
Essential (gene trap)
N
Indispensability pred.
E
Indispensability score
0.900

Gene Damage Prediction

AllRecessiveDominant
MendelianMediumMediumMedium
Primary ImmunodeficiencyMediumMediumMedium
CancerMediumMediumMedium
Feedback | API | MCP | Annotate VCF | Sitemap | About | Privacy & Terms
For research and educational, non-commercial use only. Not for clinical or diagnostic use. GeneBe does not provide medical advice. Data use for AI modeling is prohibited: if used, the cost is $0.001 per byte of downloaded uncompressed data.